JP5584316B2 - Method of suppressing myopia and application of adenylate cyclase inhibitor as a drug that suppresses myopia - Google Patents
Method of suppressing myopia and application of adenylate cyclase inhibitor as a drug that suppresses myopia Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
本発明は近視を有効に遅発、抑制する方法に係る。 The present invention relates to a method for effectively delaying and suppressing myopia.
人類の近視眼は眼軸の延長を主要な特徴としており、眼軸延長の主な部位は眼球の後極部にある。早期の研究は、正常人眼と近視眼とは、コラーゲン線維束構造、繊維直径分布及び繊維形態などの方面において共に顕著な差異を有することを発見した。現在、哺乳類動物（ツパイ、マーモセット、モルモット）の長時間の実験近視眼においても強膜が薄くなり、強膜コラーゲン繊維が細くなり、及び近視眼における内、中、外層繊維の直径分布性変化の消失の現象が見られることをすでに発見した。これらは共に、近視の発展過程において、近視眼の強膜構造の変化が１つの能動的な再建の過程を経験したことを示唆した。 Human myopic eyes are characterized by the extension of the eye axis, and the main part of the eye extension is at the posterior pole of the eyeball. Early studies have found that normal and myopic eyes both have significant differences in aspects such as collagen fiber bundle structure, fiber diameter distribution and fiber morphology. At present, in the long-term experimental myopic eyes of mammals (Tupai, marmoset, guinea pig), the sclera is thinned, the scleral collagen fibers are thinned, and the diameter distribution change of inner, middle, and outer layer fibers in myopic eyes disappears. I have already discovered that the phenomenon is seen. Both suggested that in the process of myopia development, changes in the scleral structure of the myopic eye experienced one active reconstruction process.
近年来、哺乳動物近視モデル（サル、ツパイ）の研究は、実験近視眼において繊維芽細胞の成長が抑制され、コラーゲンの合成が減少され、強膜の乾燥重量が減少されたことを示した。生物力学方面の研究はさらに、近視眼強膜の薄弱は強膜応力の変化を引き起こす可能性があることを発見した。測定の結果、近視眼の強膜の徐変が増加され、強膜の弾性が増加され、組織の破壊荷重が減少されることが確認された。以上の変化は主に後極部強膜によく見られ、最終に近視の発展を招く。 In recent years, studies of mammalian myopia models (monkeys, tupai) have shown that fibroblast growth is suppressed, collagen synthesis is reduced, and dry weight of the sclera is reduced in experimental myopic eyes. Biomechanical research further found that myopic sclera weakness can cause changes in scleral stress. As a result of the measurement, it was confirmed that the gradual change of the sclera of the myopic eye was increased, the elasticity of the sclera was increased, and the fracture load of the tissue was decreased. These changes are mainly seen in the posterior polar sclera, and ultimately lead to the development of myopia.
前記のように、強膜は現在すでに近視の発生と進展のターゲット組織と認められている。そのため、繊維芽細胞の活性化及び分化を調節することは、近視の発生及び進展に影響を与える可能性がある。Ｋｏｈｙａｍａ Ｔ， ｅｔ ａｌ．（２００２），Ｌｉｕ Ｘ， ｅｔ ａｌ．（２００４）等は細胞内のｃＡＭＰ（環状アデノシン一リン酸）の作用を調節することは肺繊維芽細胞の活性に影響を与える可能性があることを発見した。ｃＡＭＰは繊維芽細胞の活性を抑制する一部の反応において第２メッセンジャーの役割を果している。細胞内のｃＡＭＰの作用を向上することによって、肺及び心筋繊維芽細胞の分化を抑制でき、その反対に、ｃＡＭＰの作用を低減することによって、肺繊維芽細胞の活性化及び分化を促進できる。但し、現在、繊維芽細胞に対するｃＡＭＰの作用の結果がまだ報道されておらず、特に近視に対するｃＡＭＰの作用がまだ発見されなかった。 As mentioned above, the sclera is already recognized as a target tissue for the occurrence and progression of myopia. Thus, regulating fibroblast activation and differentiation can affect the occurrence and progression of myopia. Kohyama T, et al. (2002), Liu X, et al. (2004) et al. Found that modulating the action of intracellular cAMP (cyclic adenosine monophosphate) may affect the activity of lung fibroblasts. cAMP plays the role of a second messenger in some reactions that suppress fibroblast activity. By improving the action of intracellular cAMP, the differentiation of lung and myocardial fibroblasts can be suppressed, and conversely, by reducing the action of cAMP, the activation and differentiation of lung fibroblasts can be promoted. However, at present, the results of the action of cAMP on fibroblasts have not yet been reported, and in particular, the action of cAMP on myopia has not yet been discovered.
本発明の目的は眼内のｃＡＭＰの作用を低減することによって実験近視に対して干渉を行い、近視を抑制する方法を見つけることにある。 An object of the present invention is to find a method for suppressing myopia by interfering with experimental myopia by reducing the action of cAMP in the eye.
前記目的を実現するため、本発明により採用される技術的解決手段は、眼内のｃＡＭＰ作用を低減することによって近視を抑制する。 In order to achieve the object, the technical solution adopted by the present invention suppresses myopia by reducing the cAMP action in the eye.
眼内のｃＡＭＰ作用を低減する方法は通常３種を有し、第１種は、その合成を減少し、即ちアデニル酸シクラーゼ（ｃＡＭＰの合成酵素）抑制剤によって、ｃＡＭＰのレベルを減少し、現在最も常用されているのはＳＱ２２５３６である。第２種は、その分解を増加し、即ち主にＰＤＥ酵素（ｃＡＭＰを分解する）を向上することによって、ｃＡＭＰのレベルを減少する。第３種は、ｃＡＭＰの作用を拮抗し、即ちｃＡＭＰの作用下流部分で拮抗することによって、ｃＡＭＰの作用を遮断または低減する。 There are usually three ways to reduce cAMP action in the eye, the first one reduces its synthesis, ie, reduces the level of cAMP by adenylate cyclase (cAMP synthase) inhibitors, The most commonly used is SQ22536. The second species decreases the level of cAMP by increasing its degradation, i.e. mainly by improving the PDE enzyme (which degrades cAMP). The third type antagonizes the action of cAMP, ie, blocks or reduces the action of cAMP by antagonizing the downstream part of the action of cAMP.
本発明はさらに近視を抑制する新型の薬物を提供し、即ちアデニル酸シクラーゼ抑制剤を近視の抑制する薬物として応用する。 The present invention further provides a new type of drug that suppresses myopia, that is, an adenylate cyclase inhibitor is applied as a drug that suppresses myopia.
本発明の有益な効果は、眼内のｃＡＭＰの作用を低減することによって、近視を有効に遅発、抑制できる。 The beneficial effect of the present invention can effectively delay and suppress myopia by reducing the action of cAMP in the eye.
図１は実験眼と対側眼とのジオプトリーの差分図である。
図２は実験眼と対側眼との硝子体眼房の深度の差分図である。
図３は実験眼と対側眼との眼軸の長さの差分図である。
図中、「差分」は実験眼と対側眼とのジオプトリーまたは眼軸のパラメータの差分を指し、溶剤群と投与群との間の比較は一元配置分散分析（ＡＮＯＶＡ）が使用され、「＊」はＰ＜０．０５、「＊ ＊」はＰ＜０．０１、「＊ ＊ ＊」はＰ＜０．００１を表す。
FIG. 1 is a diopter difference diagram between an experimental eye and a contralateral eye.
FIG. 2 is a difference diagram of the depth of the vitreous chamber between the experimental eye and the contralateral eye.
FIG. 3 is a difference diagram of the length of the eye axis between the experimental eye and the contralateral eye.
In the figure, “difference” refers to the difference in the diopter or eye axis parameters between the experimental eye and the contralateral eye, and the one-way analysis of variance (ANOVA) is used for comparison between the solvent group and the administration group. "Represents P <0.05," ** "represents P <0.01, and" ** "represents P <0.001.
実験動物は３周齢のイギリス種三色の短毛のモルモットである。マスク法を使用して単眼形態覚遮断（ＦＤ）を行い、且つ形態覚遮断眼に対して異なる濃度（例えば１μＭ及び１００μＭ）のアデニル酸シクラーゼ抑制剤（ＡＣＩ）ＳＱ２２５３６結膜下注射を行うことによって、眼内のｃＡＭＰレベルを異なる程度に低減する。動物を、形態覚遮断対照群（ＦＤ＋ｎｏｎ−ｉｎｊｅｃｔｉｏｎ）、形態覚遮断＋溶剤対照群（ＦＤ＋ｖｅｈｉｃｌｅ）（ここの溶剤は０．９％生理塩水を指す）、形態覚遮断＋薬物群（ＦＤ＋１μＭ ＳＱ２２５３６及びＦＤ＋１００μＭ ＳＱ２２５３６群）に、ランダムに４群を分けた。毎日の午前９時に薬物を結膜下で注射し、連続に４周で注射し、対側眼が処理されない。実験前、投与２周、投与４周でそれぞれ赤外線偏心撮影光屈折測定装置（ＥＩＲ）でジオプトリー、角膜曲率メーターで角膜曲率半径、Ａモード超音波診断装置（１１ＭＨｚ）で硝子体眼房の深度及び眼軸の長さなどの眼軸パラメータを測定する。 The experimental animal is a three-lap old British three-color short-haired guinea pig. By performing monocular morphological blockade (FD) using the mask method and performing different concentrations (eg, 1 μM and 100 μM) of adenylate cyclase inhibitor (ACI) SQ22536 subconjunctival injections on the morphotropic blockage eye, Reduce cAMP levels in the eye to different degrees. Animals were divided into morphological blockade control group (FD + non-injection), morphological blockade + solvent control group (FD + vehicle) (where the solvent refers to 0.9% saline), morphological blockade + drug group (FD + 1 μM SQ22536 and FD + 100 μM). SQ22536 group) was randomly divided into 4 groups. Every day at 9 am, the drug is injected subconjunctivally and continuously for 4 laps, the contralateral eye is not processed. Before the experiment, 2 laps of administration and 4 laps of administration, respectively, diopter with infrared decentering photorefractive measuring device (EIR), corneal curvature radius with corneal curvature meter, depth of vitreous chamber with A mode ultrasonic diagnostic device (11 MHz) and Measure axial parameters such as the length of the axial axis.
実験前後の測定パラメータを比較した結果、薬物投与群の形態覚遮断眼の、屈折近視の程度及び硝子体眼房と眼軸の延長程度が共に形態覚遮断対照群及び溶剤投与群より小さく、溶剤対照群と比べて推計的有意性を有することを発見した。そのため、結膜下でアデニル酸シクラーゼ抑制剤（ＡＣＩ）ＳＱ２２５３６を注射して眼内のｃＡＭＰ作用を低減することは、モルモットの形態覚遮断性近視の形成を抑制できる。 As a result of comparing the measurement parameters before and after the experiment, the degree of refractive myopia and the extension of the vitreous chamber and the axial axis of the morphologically occluded eye in the drug administration group were both smaller than those in the morphic occlusion control group and the solvent administration group. It was found to have a statistical significance compared to the control group. Therefore, injection of adenylate cyclase inhibitor (ACI) SQ22536 under the conjunctiva to reduce the cAMP action in the eye can suppress the formation of morphine-blocking myopia in guinea pigs.
図１から分かるように、実験の４周後、単純の形態覚遮断群と形態覚遮断の溶剤注射群との近視形成量には差異が認められなかったため、注射は形態覚遮断に対して影響しないことを示した。薬物投与の２群の近視形成量が共に溶剤群より小さく、且つ時間効果及び濃度勾配効果を有するため、アデニル酸シクラーゼ抑制剤ＳＱ２２５３６が形態覚遮断性近視の形成を抑制できることを示した。 As can be seen from FIG. 1, after four laps of the experiment, there was no difference in the amount of myopia formed between the simple morphological block and the morphol blocker injection group, and therefore injection had an effect on morphblock. Indicated not to. Since the amount of myopia formation in the two groups of drug administration was both smaller than that of the solvent group and had a time effect and a concentration gradient effect, it was shown that the adenylate cyclase inhibitor SQ22536 can suppress the formation of morphotropic-blocking myopia.
図２から分かるように、実験の４周後、単純の形態覚遮断群と形態覚遮断の溶剤注射群との硝子体眼房の延長には差異が認められなかったため、注射は形態覚遮断に対して影響しないことを示した。薬物投与の２群の硝子体眼房の延長が共に溶剤群より顕著に小さく、且つ時間効果及び濃度勾配効果を有するため、アデニル酸シクラーゼ抑制剤ＳＱ２２５３６が形態覚遮断の硝子体眼房の延長を抑制できることを示した。 As can be seen from FIG. 2, after 4 laps of the experiment, there was no difference in the vitreous chamber extension between the simple morphological block and the morphotropic blocker injection group, so It was shown that it has no effect on it. Since the length of the vitreous chamber of the two groups of drug administration is both significantly smaller than that of the solvent group and has a time effect and a concentration gradient effect, the adenylate cyclase inhibitor SQ22536 prolongs the vitreous chamber of morphological blockade. It was shown that it can be suppressed.
図３から分かるように、実験の４周後、単純の形態覚遮断群と形態覚遮断の溶剤注射群との眼軸の延長には差異が認められなかったため、注射は形態覚遮断に対して影響しないことを示した。薬物投与の２群の眼軸の延長が共に溶剤群より顕著に小さく、且つ時間効果及び濃度勾配効果を有するため、アデニル酸シクラーゼ抑制剤ＳＱ２２５３６が形態覚遮断後の眼軸の延長を抑制できることを示した。 As can be seen from FIG. 3, after 4 laps of the experiment, there was no difference in the extension of the eye axis between the simple morphological blockade group and the morphol blocker injection group. Showed no effect. Since the extension of the eye axis of the two groups of drug administration is significantly smaller than that of the solvent group and has a time effect and a concentration gradient effect, the adenylate cyclase inhibitor SQ22536 can suppress the extension of the eye axis after morphological blockade. Indicated.
前記実験は、アデニル酸シクラーゼ抑制剤を使用してｃＡＭＰの作用を低減することは、近視を遅発する作用を顕著に効できることを証明した。 The experiment proved that reducing the effect of cAMP using an adenylate cyclase inhibitor can significantly reduce the effect of delaying myopia.
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| CN2010106051333A CN102078614B (en) | 2010-12-27 | 2010-12-27 | Method for inhibiting shortsightedness and application of adenylate cyclase inhibitor as medicament for inhibiting shortsightedness |
| CN201010605133.3 | 2010-12-27 | ||
| PCT/CN2011/084332 WO2012089053A1 (en) | 2010-12-27 | 2011-12-21 | Method for inhibiting myopia and use of adenylate cyclase inhibitor as drug for inhibiting myopia |
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| JPH09301891A (en) * | 1996-03-15 | 1997-11-25 | Senju Pharmaceut Co Ltd | Ocular axial length control agent, preventive and therapeutic agent for hypometropia or hypermetropia |
| EP0834308A1 (en) * | 1996-09-30 | 1998-04-08 | LG Chemical Limited | Ophthalmic formulation for treating myopia comprising dopamine agonist and cyclodextrin |
| CN1179979A (en) * | 1996-10-03 | 1998-04-29 | 株式会社Lg化学 | Ophithalmic formulation for treating myopia comprising dopamine agonist and cyclodextrin |
| SE0002211D0 (en) * | 2000-06-13 | 2000-06-13 | Synphora Ab | Methods and compositions for prevention of myopia |
| AU2003280687A1 (en) * | 2002-10-31 | 2004-05-25 | Hitoshi Niwa | Composition for culturing multipotent stem cells and utilization of the same |
| BR0316256A (en) * | 2002-11-18 | 2005-10-04 | Celgene Corp | Methods of inhibiting tnf-alpha production and pde4 activity, treating or preventing a disease or disorder, controlling camp levels in a cell and producing a compound, pharmaceutical composition and compound |
| US8313763B2 (en) * | 2004-10-04 | 2012-11-20 | Tolmar Therapeutics, Inc. | Sustained delivery formulations of rapamycin compounds |
| JP2011520872A (en) * | 2008-05-14 | 2011-07-21 | ソウル ナショナル ユニバーシティー インダストリー ファウンデーション | A composition for regulating cellular senescence comprising an inhibitor of lysophosphatidic acid and adenylyl cyclase as active ingredients |
| WO2010019450A2 (en) * | 2008-08-09 | 2010-02-18 | Nyles Bauer | Synergizing active compounds for treating inflammation and other conditions |
| KR101091849B1 (en) * | 2009-04-28 | 2011-12-12 | 서울대학교산학협력단 | A Composition for Promoting Wound Healing Comprising Lysophosphatidic acid and inhibitor of Adenylyl cyclase as Active Ingredient |
| CN102078614B (en) * | 2010-12-27 | 2012-07-25 | 温州医学院眼视光研究院 | Method for inhibiting shortsightedness and application of adenylate cyclase inhibitor as medicament for inhibiting shortsightedness |
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| EP2589386A4 (en) | 2013-06-12 |
| US9084791B2 (en) | 2015-07-21 |
| CN102078614B (en) | 2012-07-25 |
| SG181955A1 (en) | 2012-08-30 |
| EP2589386A1 (en) | 2013-05-08 |
| CN102078614A (en) | 2011-06-01 |
| JP2013517332A (en) | 2013-05-16 |
| EP2589386B1 (en) | 2015-06-17 |
| WO2012089053A1 (en) | 2012-07-05 |
| EP2589386B8 (en) | 2015-08-26 |
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